A polyglutamine aggregation-caused disease is an autosomal dominant progressive neurodegenerative disease. Abnormally expanded cytosine-adenine-guanine (CAG) repeats encoding polyglutamine are included in the gene responsible for polyglutamine aggregation-caused diseases. The translation of the gene responsible for polyglutamine aggregation-caused diseases having such abnormally expanded CAG repeats into the gene product, leads to the onset of polyglutamine aggregation-caused diseases. For example, with regard to Huntington's disease among polyglutamine aggregation-caused diseases, the huntingtin gene has been identified as a responsible gene and mapped in the short arm of chromosome 4 (see also The Huntington's Disease Collaborative Research Group, Cell, 1993; vol. 72: pp. 971-983). The huntingtin gene encodes the huntingtin protein of 3145 amino acid residues. This protein itself is expressed in various tissues and its full-length protein, which is nonpathogenic, is predominantly distributed in the cytoplasm. The CAG repeats are present in exon 1 of the huntingtin gene. When the gene is nonpathogenic, it has less than about 30 CAG repeats. The gene having about CAG repeats or more is pathogenic enough to induce Huntington's disease. From the gene with CAG repeats expanded to 30 or more, the huntingtin protein with longer glutamine repeats (polyglutamine) in the N-terminus, which is called mutant huntingtin, is produced. The mutant huntingtin with such a long stretch of polyglutamine is easy to aggregate. The long stretch of polyglutamine has been also reported to influence the interaction with other proteins and to promote the self-processing of the huntingtin protein therewith. Processed huntingtin protein is present abundantly in the nucleus, which results in toxicity to the cell and the onset of Huntington's disease. In general, Huntington's disease develops at the middle age and leads to death in 15 to 20 years after the onset. The symptom is characterized by distinctive uncoordinated muscle movement, cognitive deterioration and psychiatric symptoms, etc. The uncoordinated muscle movement is considered to result from a loss of coordination between voluntary movements and abnormal involuntary movements, including chorea and dystonia.
Meanwhile, HGF was first identified as a potent mitogen for mature hepatocytes and was determined by DNA cloning in 1989 (see also Nakamura, T., et al., Blochem. Biophys. Res. Commun., 1984; vol. 122: pp. 1450-1459 and Nakamura, T. et al., Nature, 1989; vol. 342: pp. 440-443). Kosai, K. et al. has reported that, via an anti-apoptotic effect, the administration of HGF prevents endotoxin-induced lethal hepatic failure accompanied by fulminant hepatic failure in mice (see also Hepatology 1999; vol. 30: pp. 151-159). Ueki, T. et al. has also reported that HGF gene therapy potentially improves the survival rate of rats with lethal liver cirrhosis (see also Nat. Med., 1999; vol. 5: pp. 226-230). Additionally, it has been demonstrated that HGF is also a novel neurotrophic factor through a large number of recent studies in the expression and functional analysis including knockout and knockin mice methods (see also Matsumoto, K. et al., Ciba Found. Symp., 1997; vol. 212, pp. 198-211; discussion 211-194 and Funakoshi, H. et al., Clin. Chim. Acta., 2003; vol. 327: pp. 1-23). Especially, HGF has been known to be one of the most potent survival factor for motoneurons in vitro, equivalent to glial cell line-derived neurotrophic factor (GDNF) according to Neuron, 1996; vol. 17: pp. 1157-1172. The accelerator for the GDNF production has been reported to be a therapeutic agent for amyotrophic lateral sclerosis (ALS), one of the neurodegenerative diseases according to JP-A No. 2002-47206. Further, HGF or a gene thereof has also been reported to slow the disease progression and increase the survival rate in ALS model transgenic mice, in which the expression of SOD1G93A, a human ALS-causing gene, is induced (see also JP-A No. 2002-87983 and Sun, W. et al., Brain Res. Mol. Brain. Res., 2002; vol. 103: pp. 36-48).
On the contrary, it has been known that GDNF gene delivery does not produce useful results in R6/2 Huntington's disease transgenic mice subjected to the lentivirus vector-mediated gene delivery of the GDNF gene (see also Popovic, N. et al., Exp. Neurol., 2005; vol. 193: pp. 65-74).
These facts as above indicate that polyglutamine aggregation-caused diseases such as Huntington's disease are completely different in etiology, pathology and pathogenesis mechanism, etc. from other neurodegenerative diseases including ALS, Alzheimer's disease and Parkinson's disease, and therefore all the neurodegenerative diseases cannot be treated alike.
The examples described in WO03-045439 show that the ethological and histological study was conducted as to the effects of the HGF gene on model rats of nigral dopamine neuron cell death. In the model rat, a drug administration has specifically destroyed nigral dopamine neurons in the mesencephalon, whose degeneration is typically observed in Parkinson's disease. The results of the study show that the preadministration of the HGF gene protected nigral dopamine neurons in the mesencephalon from neurotoxin 6-OHDA and inhibited the symptoms of model rats of nigral dopamine neuron cell death. Furthermore, based on these results, WO03-045439 discloses that the HGF gene is applicable to the treatment of neurodegenerative diseases such as not just Parkinson's disease, but also Alzheimer's disease, spinocerebellar ataxia, multiple sclerosis, striatonigral degeneration, spinal muscular atrophy, Huntington's disease, Shy-Drager syndrome, Charcot-Marie-Tooth disease, Friedreich's ataxia, myasthenia gravis, occlusive disease in the circle of Willis, amyloidosis, Pick's disease, subacute myelo-optico-neuropathy, dermatomyositis, multiple myositis, Creutzfeldt-Jakob disease, Behcet's disease, systemic lupus erythematosus, sarcoidosis, periarteritis nodosa, ossification of the posterior longitudinal ligament, multilevel spinal canal stenosis, mixed connective tissue disease, diabetic peripheral neuropathy and ischemic cerebrovascular disorders (cerebral infarction, cerebral hemorrhage, etc.). Huntington's disease is also listed as such a neurodegenerative disease.
However, while Parkinson's disease is a neurodegenerative disease caused by selective dropout of specific neurons, namely dopaminergic neurons in the substantia nigra, polyglutamine aggregation-caused disease develops due to the expression of the disease-causing gene product containing a long stretch of glutamine (polyglutamine) as mentioned above. The neurodegeneration or cell-death mechanism induced by 6-OHDA is totally different from that induced by the gene product responsible for polyglutamine aggregation-caused diseases. Therefore, even if HGF has the neuroprotective effects against 6-OHDA, it can be hardly expected to prevent the neurodegeneration or cell death in polyglutamine aggregation-caused diseases. From a clinical point of view, both of Parkinson's disease and a polyglutamine aggregation-caused disease are neurodegenerative diseases, but they have completely different pathologies and no correlation with each other. Additionally, their lesioned neurons are totally different. Accordingly, only the above-mentioned results of the study on Parkinson's disease model rats are not enough to say that HGF protein or DNA encoding the same is useful for the treatment of polyglutamine aggregation-caused diseases, and in fact, no reports have said so.
As mentioned above, therapeutic modalities of polyglutamine aggregation-caused diseases including Huntington's disease have not been established yet and in an extremely difficult situation.